Congenital infection with human cytomegalovirus is a major cause of brain disease and long-term sequelae in infants and children. Although the natural history of this maternal/fetal infection has been studied for over 30 years, major gaps in our understanding in the pathogenesis of this infection remain. In contrast to other congenital viral infections such as those caused by rubella, congenital CMV infections occurs in offspring of immune women. Congenital infections in immune women are termed non-primary infections and likely account for the vast majority of infected infants worldwide. Recently, several reports have indicated that congenital infections following non-primary maternal infections also are a major cause of disease in newborn infants and can be associated with long term CNS sequelae. Furthermore, the incidence of congenital CMV infections appears to increase with increasing maternal seroprevalence. In this proposal we will extend the ongoing studies in southeastern Brazil where the maternal CMV seroprevalence is >95% and the congenital infection rate is over 2%. Our goals are to identify maternal risk factors associated with this high rate of congenital infection and to begin to define the relationship between viral genetic diversity and the high rate of congenital infection. Studies such as the one proposed in this application are particularly relevant to the development of strategies such as vaccination to limit this important cause of childhood disease.